This project focuses upon inherited mechanisms regulating the catecholamine synthesizing enzymes tyrosine hydroxylase (TH), dopamine-Beta-hydroxylase (DBH), and phenylethanolamine-N-methyltransferase (PNMT). Genetic determinants have been validated for tissue enzyme levels, including serum DBH, and are suggested for processes regulating adrenal TH, DBH and PNMT activity increases in response to stress. One major area of research will assess mechanisms underlying inherited serum DBH levels in rats. We will evaluate potential sex-linkage, potential effects of maternal neuroleptic drug treatment on serum DBH in offspring, and the processes involved in serum DBH enzyme protein degradation. These studies will include refinement of methodology for estimating serum DBH clearance in different rat strains. Degradation will be studied by liver plasma membrane binding, desialylation rats, and uptake of DBH protein by liver cells. Results from these studies could serve as a model for interpreting human serum DBH data, and may offer insight into the etiology of low serum DBH in schizophrenic probands and their families. The second major area of research will assess regulation of adrenal enzymes during stress. Using breeding studies, we will determine whether pituitary-dependent and neuronally-dependent processes controlling adrenal enzyme increase to immobilization stress are heritable, and whether processes regulating TH and DBH are separable from those regulating adrenal PNMT, as indicated by our present data. We also will begin to assess brain PNMT genetics. These studies will provide insights into the role of inherited factors in metabolic alterations essential to physiologic and behavioral adaptation.